Clinical implications of pharmacogenetic research

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Clinical implications of pharmacogenetic research

• St Petersburg April 4, 2008

Professor Leif BertilssonDept. of Clinical
PharmacologyKarolinska University Hospital,
HuddingeSweden
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• Pharmacogenetics
• Pharmacogenomics

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Polymorphic impact on drug response
Drug
Drug transporters

Drug metabolising enzymes
Metabolites

Drug receptors

Drug receptor effectors

Drug response
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Johansson et al., PNAS 901945-51, 1993, Aklillu
et al., JPET 278 441-6, 1996
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Dalén et al, 1998
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Frequency of subjects having duplicated/
multiduplicated CYP2D6 genes
Sweden 1-2 Dahl et al, 1995Denmark 0.8
Bathum et al, 1998Germany 3.6 Sachse et al,
1997Spain (Badajoz) 7.0 Agundez et al,
1995Spain (Zaragoza) 10 Bernal et al,
1998Saudi Arabia 20 McLellan et al,
1997Ethiopia 29 Aklillu et al, 1996Los
Angeles, USA Caucasians 4.3 London et al,
1997 African-Americans 4.9 London et al, 1997
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Kawanishi et al 2004
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Similarity among the CYP3A proteins
CYP3A5 CYP3A7 CYP3A43CYP3A4 84.1
88.1 75.8CYP3A5 81.9
75.8CYP3A7
71.5CYP3A43
Gellner et al 2001
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Plasma concentrations of cholesterol and
4?-hydroxycholesterol in patients treated with
different antiepileptics 
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4ß-Hydroxycholesterol in three populations
plt0.000001
plt0.000001
plt0.01
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Haplotype frequencies Haplotype frequencies Haplotype frequencies
3 6986AgtG 6 14690gtA 7 27131-27132insT Swedes Koreans Tanzanians
CYP3A51 A G T 0.07 0.17 0.53
CYP3A53 G G T 0.93 0.80 0.17
CYP3A56 A A T - - 0.18
CYP3A57 A G TT - - 0.12
CYP3A53 7 G G TT - 0.03
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Impact of CYP3A5 on 4ß-hydroxycholesterol
Number of CYP3A51 alleles
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• Inhibition of metoprolol metabolism and
  potentiation of
• its effects by paroxetine in routinely treated
  patients with
• acute myocardial infarction (AMI)
• Ksenia Goryachkina, Aleksandra Bubello, Svetlana
  Boldueva,
• Svetlana Babak, Ulf Bergman, Leif Bertilsson
• Eur. J. Clin. Pharmacol. 200864275-282

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Methods

• 187 patients (61 men, age 6011 years (36-85)
  with confirmed AMI
• CYP2D6 3,4, and gene duplication
• Metoprolol and a-hydroxy metoprolol
  concentrations were measured in plasma 0,2,6 and
  12 hours after metoprolol intake
• Heart rate and blood pressure was measured at the
  times of sampling
• Clinical variables were taken from case histories
  (baseline and discharge heart rate, metoprolol
  dose at discharge, concomitant diseases, severity
  of AMI, heart failure etc)

Pharmacodynamics
Pharmacokinetics
Heart rates on the adjusted metoprolol dose were
higher with more functional alleles (plt0.05)
Metoprolol plasma concentration AUC Is determined
by CYP2D6 genotype Plt0.001
number of functional CYP2D6 alleles
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Goryachkina et al, 2008
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Active CYP2D6 genes in AMI patients
withoutventricular rhythm disturbances (VRD)
(n177)and with VDR (N23) in hospitalized
Russian patients
CYP2D6 duplication 4/173 (2 )
5/18
(22 )
p 0.0002
Goryachkina et al, 2008
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Bertilsson et al Debrisoquine hydroxylation and
personality, Lancet 1989 Poor hydroxylators had
significantly lower scores in the Karolinska
psychasthenia scale (plt0.05) and had a higher
frequency of extreme responses (plt0.01) than
extensive hydroxylators. Low psychasthenia scores
imply high vitality, alertness, efficiency, and
ease of decision-making. The poor hydroxylators
lack of hesitation was also reflected in the more
frequent choice of extremes. These personality
characteristics agreed well with the impression
we had before our study.